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Maintenance Treatment Study Designs in Bipolar Disorder

Do They Demonstrate that Atypical Neuroleptics (Antipsychotics) are Mood Stabilizers?

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Abstract

In this conceptual review we argue that by certifying some of the atypical neuroleptics (or, if one prefers, antipsychotics) as indicated for the ‘maintenance’ treatment of bipolar disorder, the US FDA has created confusion in the field. These maintenance indications are based on studies using a ‘relapse prevention’ design, a design that does not address whether the agents tested can prevent new episodes of illness, i.e. recurrence prevention or true prophylaxis.

We found that the relapse prevention design fails to prove that these agents are mood stabilizers because patients are pre-selected to respond to the study drug for an acute mood episode (mania) and when they relapse, they do so into an episode of the same polarity (i.e. mania). We believe that this represents withdrawal into the same mood episode that patients experienced before the maintenance study began, rather than prevention of a new mood episode, as research into the natural history of bipolar disorder indicates that such new episodes typically are of the opposite polarity. Thus, the inability of neuroleptics to prevent depression in such maintenance studies reflects the general inability to prevent any new mood episode recurrence (which we believe should be defined as 6 months or longer after the index episode).

If one defines a mood stabilizer, as we do, as a drug that prevents new episodes of mania and depression in monotherapy, then these studies do not show that atypical neuroleptics are mood stabilizers. Future maintenance research studies in bipolar disorder should use the prophylaxis design (i.e. without pre-selection of drug responders), rather than the relapse prevention design.

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References

  1. Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry 2004 Mar; 65(3): 432–41

    Article  PubMed  CAS  Google Scholar 

  2. Tohen M, Calabrese JR, Sachs GS, et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry 2006 Feb; 163(2): 247–56

    Article  PubMed  Google Scholar 

  3. Keck Jr PE, Calabrese JR, McIntyre RS, et al. Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo. J Clin Psychiatry 2007 Oct; 68(10): 1480–91

    Article  PubMed  CAS  Google Scholar 

  4. Bowden C, Swann A, Calabrese J, et al. Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study. Psychopharmacol Bull 1997; 33: 693–9

    PubMed  CAS  Google Scholar 

  5. Calabrese JR, Rapport DJ. Mood stabilizers and the evolution of maintenance study designs in bipolar I disorder. J Clin Psychiatry 1999; 60 Suppl. 5: 5–13, discussion 4-5

    Google Scholar 

  6. Goodwin F, Jamison K. Manic depressive illness. 2nd ed. New York (NY): Oxford University Press, 2007

    Google Scholar 

  7. Ghaemi SN. On defining ‘mood stabilizer’. Bipolar Disord 2001; 3(3): 154–8

    Article  PubMed  CAS  Google Scholar 

  8. Ayd FJ, editor. Lexicon of psychiatry, neurology, and the neuroscience. Philadelphia (PA): Lippincott, Williams, and Wilkins, 2000

    Google Scholar 

  9. Suppes T, Baldessarini RJ, Faedda GL, et al. Risk of reoccurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry 1991; 48: 1082–8

    Article  PubMed  CAS  Google Scholar 

  10. Cavanagh J, Smyth R, Goodwin GM. Relapse into mania or depression following lithium discontinuation: a 7-year follow-up. Acta Psychiatr Scand 2004 Feb; 109(2): 91–5

    Article  PubMed  CAS  Google Scholar 

  11. Tohen M, Frank E, Bowden CL, et al. The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders. Bipolar Disord 2009 Aug; 11(5): 453–73

    Article  PubMed  Google Scholar 

  12. Bowden C, Calabrese J, McElroy S, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry 2000; 57: 481–9

    Article  PubMed  CAS  Google Scholar 

  13. Bowden C, Calabrese J, Sachs G, et al., Lamictal 606 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003; 60: 392–400

    Article  PubMed  CAS  Google Scholar 

  14. Calabrese JR, Bowden CL, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 2003 Sep; 64(9): 1013–24

    Article  PubMed  CAS  Google Scholar 

  15. Calabrese JR, Vieta E, El-Mallakh R, et al. Mood state at study entry as predictor of the polarity of relapse in bipolar disorder. Biol Psychiatry 2004 Dec 15; 56(12): 957–63

    Article  PubMed  Google Scholar 

  16. Friedman LM, Furberg CD, DeMets DL. Fundamentals of clinical trials. 3rd ed. New York (NY): Springer-Verlag, 1998

    Google Scholar 

  17. Calabrese JR, Goldberg JF, Ketter TA, et al. Recurrence in bipolar I disorder: a post hoc analysis excluding relapses in two double-blind maintenance studies. Biol Psychiatry 2006 Jun 1; 59(11): 1061–4

    Article  PubMed  CAS  Google Scholar 

  18. Macfadden W, Alphs L, Haskins JT, et al. A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disord 2009 Dec; 11(8): 827–39

    Article  PubMed  CAS  Google Scholar 

  19. Quiroz J, Lakshmi Y, Palumbo J, et al. Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder. Biol Psychiatry 2010; 68: 156–62

    Article  PubMed  CAS  Google Scholar 

  20. Pfizer, Data on file, 2010

  21. Weisler R, Nolen W, Neijber A, et al. Quetiapine or lithium versus placebo for maintenance treatment of bipolar I disorder after stabilization on quetiapine. 60th Institute on Psychiatric Services Congress; 2008 Oct 2–5; Chicago (IL)

  22. Bang H, Davis CE. On estimating treatment effects under non-compliance in randomized clinical trials: are intent-to-treat or instrumental variables analyses perfect solutions? Stat Med 2007 Feb 28; 26(5): 954–64

    Article  PubMed  Google Scholar 

  23. Tanaka Y, Matsuyama Y, Ohashi Y. Estimation of treatment effect adjusting for treatment changes using the intensity score method: application to a large primary prevention study for coronary events (MEGA study). Stat Med 2008 May 10; 27(10): 1718–33

    Article  PubMed  Google Scholar 

  24. Peduzzi P, Detre K, Wittes J, et al. Intent-to-treat analysis and the problem of crossovers: an example from the Veterans Administration coronary bypass surgery study. J Thorac Cardiovasc Surg 1991 Mar; 101(3): 481–7

    PubMed  CAS  Google Scholar 

  25. Deshauer D, Fergusson D, Duffy A, et al. Re-evaluation of randomized control trials of lithium monotherapy: a cohort effect. Bipolar Disord 2005 Aug; 7(4): 382–7

    Article  PubMed  CAS  Google Scholar 

  26. Geddes JR, Goodwin GM, Rendell J, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010 Jan 30; 375(9712): 385–95

    Article  PubMed  Google Scholar 

  27. Briscoe B, El-Mallakh R. The evidence base for the long-term use of antidepressants as prophylaxis against future depressive episodes [poster]. American Psychiatric Association Annual Meeting; 2010 May 23–26; New Orleans (LA)

  28. Amsterdam JD, Shults J. Efficacy and safety of long-term fluoxetine versus lithium monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study. Am J Psychiatry 2010; 167(7): 792–800

    Article  PubMed  Google Scholar 

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Acknowledgements

In the past 12 months, S.N. Ghaemi has received a research grant from Pfizer and has provided a research trial consultation for Sepracor. F.K. Goodwin is currently on the speaker’s bureau for GlaxoSmithKline South America and is a consultant for Pfizer. Prior to 2009, he served as a consultant or on advisory boards for GlaxoSmithKline, Eli Lilly, Bristol Myers Squibb, Solvay and Schering-Plough, and was on the speakers’ bureaux for GlaxoSmithKline, Pfizer, Eli Lilly and Bristol Myers Squibb. E.A. Whitham declares no competing interests. This article was partially supported by NIMH grant RO1MH078060 (S.N. Ghaemi).

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Authors and Affiliations

  1. Center on Neuroscience, Medical Progress, and Society, The George Washington University School of Medicine, Washington, DC, USA

    Frederick K. Goodwin

  2. Mood Disorders Program, Tufts Medical Center, Boston, MA, USA

    Elizabeth A. Whitham &  S. Nassir Ghaemi

  3. Department of Psychiatry, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St, Box 1007, Boston, MA, 02111, USA

    S. Nassir Ghaemi

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  1. Frederick K. Goodwin
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  2. Elizabeth A. Whitham
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  3. S. Nassir Ghaemi
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Correspondence to S. Nassir Ghaemi.

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Goodwin, F.K., Whitham, E.A. & Ghaemi, S.N. Maintenance Treatment Study Designs in Bipolar Disorder. CNS Drugs 25, 819–827 (2011). https://doi.org/10.2165/11593740-000000000-00000

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